Search

A series of phenothiazine analogues were synthesized to study the structure–activity relationship and their potency as TLK1 inhibitors for cancer therapy.

Crystal engineering of gefitinib by forming cocrystals help in modulating its physico-chemical properties while retaining its biological activity.

A cooperative cocrystal was obtained from the combination of two different aggregation-induced emitting cyanostilbene units: (Z)-3-(4-(dimethylamino)phenyl)-2-(pyridin-4-yl)acrylonitrile (Py) and (Z)-3-(4-(dimethylamino)phenyl)-2-(4-iodophenyl)acrylonitrile (MI). The co-diffraction data revealed that the cocrystals were bound by...

Context The molecular mechanism by which Swertiamarin (SM) prevents advanced glycation end products (AGEs) induced diabetic nephropathy (DN) has never been explored. Objective To evaluate the effect of SM in preventing the progression of DN in high fat diet-streptozotocin-induced diabetic rats. Materials and methods After 1 week of acclimatisation, the rats were divided randomly into five groups as follows: (1) Control group, which received normal chow diet; (2) High-fat diet (HFD) group which was fed diet comprising of 58.7% fat, 27.5% carbohydrate and 14.4% protein); (3) Aminoguanidine (AG) group which received HFD + 100 mg/k.b.w.AG (intraperitoneal); (4) Metformin (Met) group which received HFD + 70 mg/k.b.w. the oral dose of Met and (5) SM group which was supplemented orally with 50 mg/k.b.w.SM along with HFD. After 12 weeks all HFD fed animals were given a single 35 mg/k.b.w. dose of streptozotocin with continuous HFD feeding for additional 18 weeks. Later, various biochemical assays, urine analyses, histopathological analysis of kidneys, levels of AGEs, expression of various makers, and in-silico analysis were performed. Results The diabetic group demonstrated oxidative stress, increased levels of AGEs, decreased renal function, fibrosis in the renal tissue, higher expression of the receptor for advanced glycation end products (RAGE), which were ameliorated in the SM treated group. In-silico analysis suggests that SM can prevent the binding of AGEs with RAGE. Conclusions SM ameliorated DN by inhibiting the oxidative stress induced by AGEs.HighlightsSM reduces the levels of hyperglycaemia-induced advanced glycation end products in serum and renal tissue.SM prevents renal fibrosis by inhibiting the EMT in the kidney tissue.The in-silico analysis proves that SM can inhibit the binding of various AGEs with RAGE, thereby inhibiting the AGE-RAGE axis.

A series of stimuli-responsive AIEgens of tetraphenylethylene (TPE) fused imidazole derivatives (1–7) were synthesized, and their substituent controlled fluorescence properties in the solid state were explored. The structure of the synthesised compounds was characterized by NMR, mass and single crystal X-ray diffraction spectroscopy techniques. 1–7 exhibited a typical aggregation induced emissive (AIE) behaviour in the THF : water mixture. These compounds exhibited substituent dependent strong solid state fluorescence (Φf = 16.6–55.7%) with a tunable λmax between 458 and 496 nm. Chlorine substituted 6 showed the highest fluorescence efficiency (Φf = 55.7%), whereas acetyl substituted 3 exhibited the lowest fluorescence efficiency (Φf = 16.6%). All the seven compounds showed a mechanical pressure induced reversible fluorescence switching. Crushing 1–7 resulted in red shifted fluorescence, which was reversed to its initial state by heating/solvent vapour exposure. Interestingly, integration of 1–7 into a hydrophobic PMMA polymer resulted in blue shifted fluorescence at 470 nm, whereas that into hydrophilic PVA polymer resulted in red shifted fluorescence at 491 nm. Thus highly solid state emissive TPE fused imidazole compounds were prepared, and their stimuli-induced reversible fluorescence switching and polymer controlled tunable fluorescence were demonstrated.

Background: Glucose-6-phosphate isomerase (G6PI) catalyses the second step in glycolysis in the reversible interconversion of an aldohexose glucose 6-phosphate, a six membered ring moiety to a ketohexose, fructose 6-phosphate five membered ring moiety. This enzyme is of utmost importance due to its multifunctional role like neuroleukin, autocrine motility factor, etc. in various species. G6PI from Pseudomonas aeruginosa is less explored for its moonlighting properties. These properties can be predicted by studying the active site conservation of residues and their interaction with the specific ligand. Methods: Here, we study the G6PI in a self-inducible construct in bacterial expression system with its purification using Ni-NTA chromatography. The secondary structure of pure G6PI is estimated using circular dichroism to further predict the proper folding form of the protein. The bioactivity of the purified enzyme is quantified using phosphoglucose isomerase colorimetric kit with a value of 12.5 mU/mL. Differential scanning fluorimetry and isothermal titration calorimetry were employed to monitor the interaction of G6PI with its competitive inhibitor, erythrose 4-phosphate and calculated the Tm, Kd and IC50 values. Further, the homology model for the protein was prepared to study the interaction with the erythrose 4-phosphate. MD simulation of the complex was performed at 100 ns to identify the binding interactions. Results: We identified hydrogen bonds and water bridges dominating the interactions in the active site holding the protein and ligand with strong affinity. Conclusion : G6PI was successfully crystallized and data has been collected at 6Å. We are focused on improving the crystal quality for obtaining higher resolution data.

The emergence of antibiotic-resistant strains of Helicobacter pylori necessitates the development of novel therapeutic strategies to fight against its infection. Recently, the enzyme inosine-5'-monophosphate dehydrogenase (IMPDH) has emerged as a promising target to treat bacterial infections due to its crucial role in the de novo purine biosynthesis pathway. The differences between the prokaryotic and eukaryotic IMPDHs, in the NAD

The role of protein kinases is vital in diverse cellular functions. The alterations in the expression patterns of protein kinases often implicate human cancer initiation and progression. Human Tousled-like kinases (TLKs) are evolutionary kinases found in the cell signalling pathway and are involved in DNA repair, replication and chromosomal integrity. The direct association of TLKs to cancer; amplification of both TLK1/1B and TLK2 has made them viable molecular targets for anticancer therapy. Several reports demonstrate numerous functions of TLKs in development of disease via different interacting partners. However, a detailed understanding of its substrates and regulation has yet remained elusive. In this report, through preliminary biophysical and biochemical characterization, we investigate and determine the usability of the recombinant Human Tousled-like Kinase 1B-Kinase Domain (hTLK1B-KD) purified from Escherichia coli for structural and functional studies. By illustrating hTLK1B-KD as an example, our attempts to generate a stable, homogenously dephosphorylated, and catalytically active hTLK1B-KD in high yields is utilizing a bacteriophage λ protein phosphatase (LPP) coexpression system represents a fundamental step towards the structure-based design of TLK-specific inhibitors.

An anhydrous nature of benzylidene derivatives of nicotin and isonicotinamides crystal structures is determined and studied for their weak intermolecular interactions. The molecular structure is non-planar in general with the pyridine ring twisted with respect to the central hydrazone moiety. The crystal structures depict various intermolecular interactions, including N–H⋯O, C–H⋯O, N–H⋯N, and C–H⋯N hydrogen bonding along with weak C–H … π and π … π contacts. Further, Hirshfeld surface and 2D-fingerprint plot analysis confirm the role of intermolecular interactions in building the crystal packing in these derivatives. The PIXELC energy calculation shows that dispersion energy plays an essential role in stabilizing the crystal packing in all six derivatives.

Pyridyl acrylonitrile without traditional auxiliary groups form stable organogels in ethanol. The addition of a second non-gelating cyanostilbene component results in a more stable two-component gel. Single crystal X-ray data reveal the influence of C-H⋅ ⋅ ⋅N, C-H⋅ ⋅ ⋅π, and π-π interactions in the formation of organogels. The morphology of the xerogels was studied by using SEM, which showed the self-assembly of molecules to fibers and sheet-like structures, and phase differences upon the gel formation and the structural phase characterization was measured using powder XRD. Exposure of the organogels to acidic (TFA) vapors results in distinct color changes and loss of gelation properties, thus highlighting the potential of these gels in sensing. The results represent a rare example of two-component organogels using two different cyanostilbene units and show that functional two-component organogels can be formed by utilizing the synergistic effects of the individual components.

Construction of a water-soluble, oxygen-tolerant, and acid-stable synthetic H2 production catalyst is vital for the development of an economic and user-friendly H2-based renewable energy infrastructure. Natural enzyme hydrogenases exhibit excellent energy-efficient H2 production activity. However, fragility of the overall protein structure has restricted their sustainable and practical application. Among the synthetic functional models of hydrogenase, cobaloxime-based complexes offer O2-insensitivity. However, they are only active near neutral conditions with moderate rates and poor aqueous solubility properties. Here, in this work, we have specifically stationed a series of enzyme-inspired, multicomponent outer coordination sphere components around the cobaloxime core to simultaneously improve its catalytic rate, aqueous solubility, and activity even under acidic conditions. We have also established that cobaloximes display catalytic H2 production via two independent mechanisms: (i) Co(II)-centric and (i...

CD151 is an abundantly expressed eukaryotic transmembrane protein on the cell surface. It is involved in cell adhesion, angiogenesis and signal transduction as well in disease conditions such as cancer and viral infections. However, the molecular mechanism of CD151 activation is poorly understood due to the lack of structural information. By considering the difficulties in expressing the membrane protein in E. coli, herein we introduce the strategic design for the effective expression of recombinant CD151 protein in E. coli with high yield, that would aid for the structural studies. CD151 having four transmembrane domain (TMD's) along with small and a large extracellular loop (LEL) is constructed in parts to enhance the soluble expression of the protein attached with fusion tag. This has led to the high yield of the recombinant CD151 protein in the designed constructs. The recombinant CD151 protein is characterized and confirmed by western blot, CD and Mass peptide fingerprint. The molecular dynamics simulations (MDS) for the full-length CD151 shows conformational changes in the LEL of the protein in the presence and absence of cholesterol and indicate the certainty of closed and open conformation of CD151 based on cholesterol binding. The MDS results have led to the understanding of the possible underlying mechanism for the activation of the CD151 protein.

The crystal structures of four derivatives of diethyl 2-(((aryl)amino)methylene)malonate (DAM) have been studied by single crystal X-ray diffraction. The molecular structures of all the four derivatives were found to be in co-planar conformation. The detailed analysis of molecular conformation in four derivatives reveals the presence of a common strong intramolecular N–H⋯O hydrogen bonding, forming a ring of graph-set motif S11 (6). The effect of chloro and nitro substitution on their relative strengths of hydrogen bonding are analyzed here. Particularly, in compound 1, additional intramolecular hydrogen bonding between –NO2 and N–H was observed that results in the formation of another six-membered chelate ring. On the other hand in case of compound 3, we have observed type-I Cl⋯Cl interaction for the first time in this class of compounds. Further, Hirshfeld surface has been generated that is mapped with dnorm shape index and curvedness to summarize the weak interactions and examine the molecular shapes in all four derivatives. Effect of nitro (1 and 2) and chloro (3 and 4) substitution on the C⋯H, N⋯O and C⋯O interaction is highlighted in molecular contour and 2D fingerprint plots.

Background & Objective:Helicobacter pylori infection is one of the primary causes of peptic ulcer followed by gastric cancer in the world population. Due to increased occurrences of multi-drug resistance to the currently available antibiotics, there is an urgent need for a new class of drugs against H. pylori. Inosine 5′-monophosphate dehydrogenase (IMPDH), a metabolic enzyme plays a significant role in cell proliferation and cell growth. It catalyses guanine nucleotide synthesis. IMPDH enzyme has been exploited as a target for antiviral, anticancer and immunosuppressive drugs. Recently, bacterial IMPDH has been studied as a potential target for treating bacterial infections. Differences in the structural and kinetic parameters of the eukaryotic and prokaryotic IMPDH make it possible to target bacterial enzyme selectively.Methods:In the current work, we have synthesised and studied the effect of substituted 3-aryldiazenyl indoles on Helicobacter pylori IMPDH (HpIMPDH) activity. The synthesised molecules were examined for their inhibitory potential against recombinant HpIMPDH.Results:In this study, compounds 1 and 2 were found to be the most potent inhibitors amongst the database with IC50 of 0.8 ± 0.02µM and 1 ± 0.03 µM, respectively.Conclusion:When compared to the most potent known HpIMPDH inhibitor molecule C91, 1 was only four-fold less potent and can be a good lead for further development of selective and potent inhibitors of HpIMPDH.

Impacts are prevalent in the solar system and have played a profound role in the evolution of the solar system bodies. The delivery of prebiotic compounds through impact events is thought to be a crucial step in developing habitable conditions on a planetary surface. Impact events are, therefore, significant in our understanding of the origins of life on Earth or elsewhere. Previous studies have reported the role of the impact process in the abiotic synthesis of building blocks of life, such as amino acids [1-3] and peptides [4, 5]. Here, we report the results of an experimental investigation simulating hypervelocity impacts in the laboratory on an icy mixture of amino acids. Various batches of amino acid mixtures within water ice targets, mimicking the icy bodies (140 K), were prepared and a spherical bullet of size 1 mm was fired at a speed of approximately 5 km s-1 using the light gas gun facility at the University of Kent [6]. Extremely high pressure of 10’s of gigapascals is achieved within a very short time scale as might be expected to be achieved under impact-induced shock conditions. After the impact, the ejected material from the target was collected and analyzed. When these ejecta was subjected to a Scanning Electron Microscope (SEM) analysis, it revealed ordered structures with interesting morphological features. A SEM micrograph of amino acid glutamine ejecta consisting of dendritic patterns is shown in Figure 1. LCMS analysis of ejecta residue shows that long polypeptide is synthesized as a result of impact. Figure 1 SEM micrographs of ejecta after impact from glutamine-water ice target shows dendritic patterns with several branching structures. The ability of shocked amino acids to form polypeptides assembled in the form of complex macroscale structures provides evidence for the evolution of the building blocks of life under impact-shock conditions. Peptides play a crucial role in the origin of life because of their unique architecture and self-assembling properties [7] and thus, prebiotic availability of peptides is believed to be crucial for the origin of life. The present results provide another step in the elucidation of our understanding of the role played by complex molecules and impact events in the origin of life. References 1. Bar-Nun, A., et al., Shock synthesis of amino acids in simulated primitive environments. Science, 1970. 168(3930): p. 470-472. 2. Furukawa, Y., et al., Biomolecule formation by oceanic impacts on early Earth. Nature Geoscience, 2009. 2(1): p. 62-66. 3. Martins, Z., et al., Shock synthesis of amino acids from impacting cometary and icy planet surface analogues. Nature Geoscience, 2013. 6(12): p. 1045-1049. 4. Sugahara, H. and K. Mimura, Peptide synthesis triggered by comet impacts: A possible method for peptide delivery to the early Earth and icy satellites. Icarus, 2015. 257: p. 103-112. 5. Sugahara, H. and K. Mimura, Glycine oligomerization up to triglycine by shock experiments simulating comet impacts. Geochemical Journal, 2014. 48(1): p. 51-62. 6. Burchell, M.J., et al., Hypervelocity impact studies using the 2 MV Van de Graaff accelerator and two-stage light gas gun of the University of Kent at Canterbury. Measurement Science and Technology, 1999. 10(1): p. 41. 7. Frenkel-Pinter, M., et al., Prebiotic Peptides: Molecular Hubs in the Origin of Life. Chemical Reviews, 2020.

This article belongs to the Special Issue Molecular Spectroscopy and Molecular Structure: Commemorative Issue in Honor of Professor Austin J. Barnes on Occasion of his 75th Birthday, In this report, we describe the structural characterization of three 2,4-disubstituted-dihydropyrimidine-5-carbonitrile derivatives, namely 2-{[(4-nitrophenyl)methyl]sulfanyl}-6-oxo-4-propyl-1,6-dihydropyrimidine-5-carbonitrile 1, 4-(2-methylpropyl)-2-{[(4-nitrophenyl)methyl]sulfanyl}-6-oxo-1,6-dihydropyrimidine-5-carbonitrile 2, and 2-[(2-ethoxyethyl)sulfanyl]-6-oxo-4-phenyl-1,6-dihydropyrimidine-5-carbonitrile monohydrate 3. An X-ray diffraction analysis revealed that these compounds were crystallized in the centrosymmetric space groups and adopt an L-shaped conformation. One of the compounds (3) crystallized with a water molecule. A cyclic motif (R22(8)) mediated by N–H···O hydrogen bond was formed in compounds 1 and 2, whereas the corresponding motif was not favorable, due to the water molecule, in compound 3. The crystal packing of these compounds was analyzed based on energy frameworks performed at the B3LYP/6-31G(d,p) level of theory. Various inter-contacts were characterized using the Hirshfeld surface and its associated 2D-fingerprint plots. Furthermore, a molecular docking simulation was carried out to assess the inhibitory potential of the title compounds against the human dihydrofolate reductase (DHFR) enzyme., This research was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University through the Fast-track Research Funding Program.

This manuscript shows a detailed computational approach of carefully curated drugs that can potentially act against Nsp15, an endoribonuclease necessary for SARS-CoV2 multiplication. In our work, we have considered maximum resources available on Nsp15 including the recent crystal structure solution of the protein. Owing to the increase in demand for a cure for COVID-19, we have attempted to virtually screen an important target of SARS-CoV2 using the pre-existing FDA approved drugs. The main advantage of our work is our multi-step approach in validating our hits. We have performed initial High Throughput Virtual Screening (HTVS) of 2910 drugs. The top 20 hits were subjected to rigorous molecular docking and molecular dynamics simulations yielding a final number of 5 potential hits. In this global emergency, we have made a humble yet critical attempt by undertaking this work; we hope that our work once published may be of help in carrying out appropriate wet-lab work. We declare that this manuscript is original, has not been published before and is not currently being considered for publication elsewhere."

Helicobacter pylori (H. pylori), the major cause of several gastric disorders has been recognied as a type I carcinogen. By virtue of resistance developed by H. pylori strains, currently used antibiotic based treatments rather demonstrate high failure rates. Hence, there is an emerging need for identification of new targets to treat H. pylori infection. Inosine-5′-monophosphate dehydrogenase (IMPDH) has been studied as a potential target to treat H. pylori infection. Here, a detailed enzyme kinetic study of recombinant expressed H. pylori inosine-5′-monophosphate dehydrogenase (HpIMPDH) is presented. A new in-house synthesized indole-based scaffold is identified as an inhibitor for HpIMPDH. These indole-based compounds showed non-competitive inhibition against IMP and NAD+ whereas the benzimidazole compounds were found be uncompetitive inhibitors. The new indole scaffold ensures specificity due to its high selectivity for bacterial IMPDH over human IMPDH II. Our work aims to overcome the drawback of existing inhibitors by introducing new indole scaffold for targeting bacterial IMPDH.

Human Tousled-like kinases (TLKs) are highly conserved serine/threonine protein kinases responsible for cell proliferation, DNA repair, and genome surveillance. Their possible involvement in cancer via efficient DNA repair mechanisms have made them clinically relevant molecular targets for anticancer therapy. Innovative approaches in chemical biology have played a key role in validating the importance of kinases as molecular targets. However, the detailed understanding of the protein structure and the mechanisms of protein–drug interaction through biochemical and biophysical techniques demands a method for the production of an active protein of exceptional stability and purity on a large scale. We have designed a bacterial expression system to express and purify biologically active, wild-type Human Tousled-like Kinase 1B (hTLK1B) by co-expression with the protein phosphatase from bacteriophage λ. We have obtained remarkably high amounts of the soluble and homogeneously dephosphorylated form of biologically active hTLK1B with our unique, custom-built vector design strategy. The recombinant hTLK1B can be used for the structural studies and may further facilitate the development of new TLK inhibitors for anti-cancer therapy using a structure-based drug design approach.

The title compounds include an acridone as a parent molecule in which nitrogen is linked to other nitrogen-containing heterocyclic molecules through two carbon chain alkyl linkers connected by a C—N single bond. These acridone derivatives crystallized as Triclinic, Monoclinic, Tetragonal, and Orthorhombic having space group P1, P21/c, I41/a, Pca21, respectively at T = 273 K. In the present work, synthesis and single-crystal X-ray crystallographic study of four novel acridone derivatives are reported from the perspective of crystal engineering. This work is based on the comprehensive analysis of Hirshfeld surfaces, 2D fingerprint plots, and DFT studies. The single-crystal structure analysis showed that compounds are connected by various intermolecular interactions such as C – H⋯O, C – H⋯C/π, and π⋯π (C⋯C) stacking interactions, which are accountable for the arrangement and amplification of molecular assembly. The DFT studies using the B3LYP functional with the 6-311++ G (d,p) basis set are employed to compare the experimental results with theoretically obtained molecular parameters. The HOMO and LUMO analyzes were used to elucidate information regarding molecular reactivity and charge transfer within the molecule.

Oximes are building block of organic synthesis and they have wide range applications in laboratories, industries, and pharmaceutical as antidotes. Herein we report the crystal structures of oxime derivative Beta-p-Dimethylaminodeoxybenzionoxime (I) and o-Chloro-p-dimethylaminodeoxybenzion (II) the precursor molecule of o-Chloro-p-dimethylaminodeoxybenzionoxime and their intermolecular interactions studies through Hirshfeld surface & 2D-fingerprint plot analysis along with PIXELC and DFT calculations. The packing arrangements in I and II are driven by O H⋯N and O H⋯C interactions respectively. The O H⋯N hydrogen bonding in I facilitates the formation of the dimer with the motif of R (22(6)), whereas in II absence of oxime moiety ( NOH) restricts the dimer formation. The 2D-fingerprint plot shows the close contacts for the intermolecular interactions in I & II. The PIXELC calculation of II suggests O H⋯C contributes for intermolecular interaction that stabilizes the crystal packing with the total energy value of 60.4 kcal/mol. The DFT calculation using B3LYP with 6-311G (d, p) functional set for both the derivatives shows a small deviation in the benzene ring (I) and chlorobenzene ring (II) with the RMSD value of 0.5095 A and 0.8472 A respectively.

In the title isoxazole derivative, the phenyl and isoxazole rings are in the same plane, as indicated by the C—C—C—O torsion angle of 0.1 (3)°. The ester group has an extended conformation and is almost in the same plane with respect to the isoxazole ring, as indicated by the O—C—C—N torsion angle of −172.86 (18)°., The title compound, C12H11NO3, is an inter­mediate used in the synthesis of many drug-like mol­ecules. The mol­ecule is almost planar, with the phenyl ring inclined to the isoxazole ring by 0.5 (1)°. The ester moiety has an extended conformation and is almost in the same plane with respect to the isoxazole ring, as indicated by the O—C—C—N torsion angle of −172.86 (18)°. In the crystal, mol­ecules are linked via pairs of C—H⋯O hydrogen bonds with the same acceptor atom, forming inversion dimers with two R 2 1(7) ring motifs. The mol­ecules stack in layers lying parallel to (10-3). Analysis using Hirshfeld surface generation and two-dimensional fingerprint plots explores the distribution of weak inter­molecular inter­actions in the crystal structure.

Glucose-6-phosphate isomerase (G6PI) catalyses the second step in glycolysis in the reversible interconversion of an aldohexose glucose 6-phosphate, a six membered ring moiety to a ketohexose, fructose 6-phosphate five membered ring moiety. This enzyme is of utmost importance due to its multifunctional role like neuroleukin, autocrine motility factor, etc. in various species. G6PI from Pseudomonas aeruginosa is less explored for its moonlighting properties. These properties can be predicted by studying the active site conservation of residues and their interaction with the specific ligand.Here, we study the G6PI in a self-inducible construct in bacterial expression system with its purification using Ni-NTA chromatography. The secondary structure of pure G6PI is estimated using circular dichroism to further predict the proper folding form of the protein. The bioactivity of the purified enzyme is quantified using phosphoglucose isomerase colorimetric kit with a value of 12.5 mU/mL. Differential scanning fluorimetry and isothermal titration calorimetry were employed to monitor the interaction of G6PI with its competitive inhibitor, erythrose 4-phosphate and calculated the Tm, Kd and IC50 values. Further, the homology model for the protein was prepared to study the interaction with the erythrose 4-phosphate. MD simulation of the complex was performed at 100 ns to identify the binding interactions.We identified hydrogen bonds and water bridges dominating the interactions in the active site holding the protein and ligand with strong affinity.G6PI was successfully crystallized and data has been collected at 6Å. We are focused on improving the crystal quality for obtaining higher resolution data.

Gamma secretase activating protein (GSAP) present in β-amyloid pathway orchestrates the formation of β-amyloid plaques by γ-secretase activation and is an emerging therapeutic target for the treatment of Alzheimer's disease. It forms a ternary complex with γ-secretase and APP C-99. However, there are limited reports for the interaction of APP C-99 with GSAP. Here, we report the characterization of purified maltose binding protein (MBP) tagged human GSAP and its interaction with synthetic APP C-99 peptide fragments (712IATVIVITLVMLKKQ727 (712IQ727), 719TLVMLKKKQYTSIHHGVVEVDAAVT743 (719TT743) 734GVVEVDAAVTPEERHLSKMQQNGY757 (734GY757), and 746ERHLSKMQQNGYENPTYKFFEQMQN770 (746EN770)). The results emphasize the selective interaction of peptide (719TT743) with MBP-GSAP with a dissociation constant of 0.136 μM. Further, computational modeling of the GSAP-719TT743 complex finds an optimal bound pose of 719TT743 within an extended groove on the surface of GSAP. The preliminary results highlight the interaction between the two major proteins in the plausible ternary complex: APP C-99-GSAP-γ-secretase. It paves a futuristic path to investigate the GSAP-APP C-99 binding in detail and accentuates the role of GSAP in the β-amyloid pathway.

Sulfonylureas provide a useful motif for carrying donor and acceptor sites capable of hydrogen bonding. These are a prominent class of therapeutic agents in the pharmaceutical industry. However, the use of aryl sulfonyl oligomers in drug discovery, supramolecular chemistry and crystal engineering are unexplored. This motivated us to design, synthesize and understand the structural features of aryl sulfonylurea oligomers (n = 1–3). Here, we report the synthesis and spectroscopic characterization details such as 1H NMR, 13C NMR, mass spectrometry and single-crystal X-ray diffraction analysis for three sulfonylurea oligomer derivatives. Further, the molecular packing analysis of three derivatives reveals the significance of N H…O and C H…O intra and intermolecular hydrogen bonding. These hydrogen bonding contacts enable the sulfonylurea derivatives to form 2D framework/architecture. We quantify various intermolecular interactions in these derivatives by Hirshfeld analysis and 2D fingerprint plots. We have performed in-silico docking studies against Plasmodium falciparum (Pf) prolyl-tRNA synthetase (ProRS) to rationalize the binding affinity of title compounds.

The syntheses of newmyo-inositol derivatives have received much attention due to their important biological activities. 1,2-O-Cyclohexylidene-myo-inositol is an important intermediate formed during the syntheses of certainmyo-inositol derivatives. We report herein the crystal structure of 1,2-O-cyclohexylidene-myo-inositol dihydrate, C12H20O6·2H2O, which is an intermediate formed during the syntheses ofmyo-inositol phosphate derivatives, to demonstrate the participation of water molecules and hydroxy groups in the formation of several intermolecular O—H...O interactions, and to determine a low-energy conformation. The titlemyo-inositol derivative crystallizes with two water molecules in the asymmetric unit in the space groupC2/c, withZ= 8. The water molecules facilitate the formation of an extensive O—H...O hydrogen-bonding network that assists in the formation of a dense crystal packing. Furthermore, geometrical optimization and frequency analysis was carried out using density functional theory (DFT) calculations with B3LYP hybrid functionals and 6-31G(d), 6-31G(d,p) and 6-311G(d,p) basis sets. The theoretical and experimental structures were found to be very similar, with only slight deviations. The intermolecular interactions were quantitatively analysed using Hirshfeld surface analysis and 2D (two-dimensional) fingerplot plots, and the total lattice energy was calculated.

Two derivatives of pyrazole have been synthesized with one of the systematic substitutions made on the ortho position of the phenyl ring attached to the pyrazole moiety and characterised via single crystal X-ray diffraction. The nature of the molecules appear as planar with the hydrogen bonding features analysed quantitatively. The derivatives are geometrically optimized and studied for its molecular confirmation at the B3LYP/6-311G (d,p). The structure overlay, molecular packing and intermolecular hydrogen bonding are studied quantitatively using Hirshfeld surface and 2D fingerprint plots. In both the compounds, packing of the molecules is derived via strong O–H···N and weak C–H···O, C–H···π interactions stabilizing the packing. Further, the structure overlay between the experimental structures and the geometrically optimized structures along with frequency analysis at the quantum chemical level shows the deviation in the central pyrazole moiety and the substituted phenyl ring with the RMSD value of 0.5051 and 0.6305 A respectively. The lattice energy is calculated for both the compounds using PIXELC module in Coulomb–London–Pauli (CLP) package and is partitioned into corresponding coulombic, polarization, dispersion and repulsion contributions.

Pyridopyrimidinones are class of heterocyclic compounds which serves as important precursors in organic transformation and medicinal chemistry. In the current work three derivatives of pyrido[1,2-a]pyrimidine-3-carboxylates (1, 2 and 3) has been synthesized and characterized by NMR. The crystal structure of compound 1 (C12H12N2O3.HCl) and 2 (2(C12H12N2O3)) were solved in monoclinic system with P21/c space group and 3 (C11H9BrN2O3) shows concomitant polymorphism and solved in orthorhombic system with Pna21 and Pca21. The weak C—H⋯O and C—H…N intermolecular interactions play significant role in crystal packing of 4-Oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylates. Replacement of methyl group in compound 1 with Bromine atom resulted 3 with increased π…π stacking interactions. The unexpected concomitant polymorphic forms of compounds 3 with details of the crystal structures and supramolecular features are presented. In addition, Hirshfeld surface and 2D fingerprint plots were performed to understand the various intermolecular non-covalent interactions in pyrido[1,2-a]pyrimidine-3-carboxylates.

A series of 10H-substituted phenothiazine-based molecules were prepared by the base-catalyzed reactions. The synthesized compounds are characterized by Mass spectroscopy, NMR, and SCXRD to examine the role of different functional groups involved in the intermolecular interactions and conformational geometries. The crystal packing of the compounds is governed by O–H⋯O, C–H⋯O, and π–π interactions. A complete understanding of the intermolecular interactions is studied employing the Hirshfeld analysis, 2D Fingerprint plot. Furthermore, the density functional theory (DFT/B3LYP) method at the 6–311++G(d,p) basis set was performed to support and compare experimental & theoretical geometrical parameters of phenothiazine derivatives.

Inosine 5′-monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) catalyzes a crucial step in guanine nucleotide biosynthesis, thereby governing cell proliferation. In contrast to mammalian IMPDHs, microbial IMPDHs are relatively less explored as potential targets for antimicrobial drug discovery. In continuation with our previous work, here we report the discovery of moderately potent and highly selective Helicobacter pylori IMPDH (HpIMPDH) inhibitors. The present study is mainly focused around our previously identified, modestly potent and relatively nonselective (for HpIMPDH over human IMPDH2) hit molecule IX (16i). In an attempt to optimize the selectivity for the bacterial enzyme, we screened a set of 48 redesigned new chemical entities (NCEs) belonging to 5-aminoisobenzofuran-1(3H)-one series for their in vitro HpIMPDH and human IMPDH2 inhibition. A total of 12 compounds (hits) demonstrated ≥70% HpIMPDH inhibition at 10 μM concentration; none of the hits were active against hIMPDH2. Compound 24 was found to be the most potent and selective molecule (HpIMPDH IC50 = 2.21 µM) in the series. The study reaffirmed the utility of 5-aminoisobenzofuran-1(3H)-one as a promising scaffold with great potential for further development of potent and selective HpIMPDH inhibitors.

Inosine 5'-monophosphate dehydrogenase (IMPDH) catalyzes a crucial step in the biosynthesis of guanine nucleotides. Being a validated target for immunosuppressive, antiviral, and anticancer drug development, lately it has been exploited as a promising target for antimicrobial therapy. Extending our previous work on Mycobacterium tuberculosis IMPDH, GuaB2, inhibitor development, we screened a set of 23 new chemical entities (NCEs) with substituted flavone (Series 1) and 1,2,3-triazole (Series 2) core structures for their in vitro Helicobacter pylori IMPDH (HpIMPDH) and human IMPDH2 (hIMPDH2) inhibitory activities. All the NCEs possessed acceptable molecular, physicochemical, and toxicity property profiles. The ranges for HpIMPDH and hIMPDH2 inhibition were 9-99.9% and 16-57%, respectively, at 10 μM concentration. The most potent HpIMPDH inhibitor, 25c, exhibited IC50 value of 1.27 μM with no hIMPDH2 inhibitory activity. The moderately potent, structurally novel hit molecule, 25c, may serve as a lead for further design and development of highly potent HpIMPDH inhibitors.

Gefitinib or Iressa is an orally administered anilinoquinazoline used in cancer chemotherapy for the treatment of lung and breast cancer. It is reported to exist in two polymorphic forms, a stable form I and a metastable form II. Both of the forms belong to the triclinic P\overline{1} space group. In this work, we report the crystallization of Gefitinib to form a methanol solvate [systematic name: N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-4-amine methanol hemisolvate, C22H24ClFN4O3·0.5CH3OH] that was theoretically and experimentally investigated. The unit cell is composed of two independent Gefitinib molecules (A and B) that form a stable molecular complex with methanol in the crystal lattice. To understand the crystal lattice stabilization, a combination of techniques, namely X-ray diffraction, IR spectroscopy, thermogravimetric/differential scanning calorimetry (TG-DSC), Hirshfeld surface analysis and CLP-PIXEL methods were used. The analysis of the crystal structure of this dimer revealed a three-dimensional isostructurality with the already reported form II. The A and B molecules are connected via trifurcated C—H...O and N—H...O hydrogen bonding. In addition, the presence of the methanol molecule stabilizes the crystal structure via C—H...O, N—H...O and C—H...Cl interactions between the two monomers. The IR analysis of the dimer has shown characteristic fingerprint values when compared to the commercial form. The TG-DSC analysis of the solvated dimer is in good agreement with the patent reporting cocrystals of Gefitinib. Finally, theoretical calculations by the CLP-PIXEL method and Hirshfeld surface and two-dimensional (2D) fingerprint plot analysis were carried out in order to quantify the different intermolecular interactions and their energies in the crystal packing.

α-Cyanostilbene substituted with dimethylaniline and hydroxyl groups exhibits profound intensity enhanced bathochromic shifts in an aqueous medium as compared to organic solvents. These conspicuous emission changes are attributed to aggregation as a consequence of restricted intramolecular rotation. This observation is commonly termed as aggregation induced enhanced emission (AIEE). Single crystal X-ray crystallographic data suggest a zigzag molecular packing arrangement with intermolecular hydrogen bonding between –CN and –OH moieties. This unique observation is exploited as a diagnostic tool to probe amphiphilic compounds in aqueous media. Fluorescence investigations reveal that at lower surfactant concentrations emission due to aggregation is preserved, while at higher surfactant concentrations the aggregated emission is lost with concomitant changes to the micelle structure. Dynamic light scattering (DLS) and Scanning Electron Microscopy (SEM) experiments were used to examine the effect of surfactants on the particle size and morphology, respectively. This sensitive AIEE fluorescence response can also be visually observed by using a hand-held UV lamp.

This chapter introduces the basic concepts of nano science to readers. Some novel methodologies for synthesizing nano particles are discussed briefly. Since the book title suggests diverse applications of nano materials, this chapter also summarizes the applications of nano technology in medicine (nano medicine), where tissue engineering and regenerative medicine are discussed. Other applications DNA nanotechnology in living organisms are discussed briefly. Overall, this chapter introduces the readers to broad sections of nano science and its applications in chemistry, engineering, and medicine.

Crystals of a new salt in 2:1 ratio of 2-aminopyridine and malonic acid are grown by slow evaporation. These crystals of bis(2-aminopyridinium) malonate are orthorhombic and belong to the non-centrosymmetric space group, Fdd2 with parameters a = 22.0786(6), b = 23.0218(6), c = 5.5595(1)angstrom and Z=8 at 300 K. The crystals are isostructural to those of bis(2-aminopyridinium) maleate, which is a NLO material. The isostructurality index between bis(2-aminopyridinium) maleate and bis(2-aminopyridinium) malonate was also calculated. The hyperpolarizability calculated using semi empirical method MOPAC2009 showed that bis(2-aminopyridinium) malonate has slightly higher beta value compared to that of bis(2-aminopyridinium) maleate. (C) 2011 Elsevier B.V. All rights reserved.

Novel chromogenic thiourea based sensors 4,4'-bis-[3-(4-nitrophenyl) thiourea] diphenyl ether 1 and 4,4'-bis-[3-(4-nitrophenyl) thiourea] diphenyl methane 2 having nitrophenyl group as signaling unit have been synthesized and characterized by spectroscopic techniques and X-ray crystallography. The both sensors show visual detection, UV-vis and NMR spectral changes in presence of fluoride and cyanide anions in organic solvent as well as in aqueous medium. The absorption spectra indicated the formation of complex between host and guest is in 1:2 stoichiometric ratios. (C) 2010 Elsevier B.V. All rights reserved.

Malaria is the one most important parasitic disease of humans, which affects approximately one hundred countries and threatens half of the world’s population. The Plasmodium aspartic protease called plasmepsins performs a vital role in providing nutrients to the malaria parasite, which make these proteins as an excellent drug target. In this study, we have carried out a comparative protein modeling, active site analysis and structural analysis of all ten plasmepsins from Plasmodium falciparum. In this report we have analyzed in-silico structure modeling and made efforts to characterize plasmepsins structure and further propose its functional information. The phylogenetic analysis and disulfide linkages indicate, plasmepsin I to IV and HAP have similar structure, function property. Whereas, plasmepsin IX to X and plasmepsin VI to VIII belong to a separate cluster. The integral membrane protein plasmepsin V has a functional characterization as compared to the others aspartic proteases from Plasmodium falciparum. The overall study summarizes the need of good model to understand the structure and function activity and to design potent small molecule inhibitors targeting all ten plasmepsins, specifically Plasmepsin V as important target.